Structural Basis for the Distinct Membrane Binding Activity of the Homologous C2A Domains of Myoferlin and Dysferlin
Structural Basis for the Distinct Membrane Binding Activity of the Homologous C2A Domains of Myoferlin and Dysferlin
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DOI：
10.1016/j.jmb.2019.04.006
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发表时间：
2019-05-17
影响因子：
5.6
通讯作者：
Sutton, R. Bryan
中科院分区：
文献类型：
--
作者：
Harsini, Faraz M.;Bui, Anthony A.;Sutton, R. Bryan
异铁蛋白与急性膜修复过程有关，而肌铁蛋白的活性在早期骨骼肌细胞发育的成肌细胞融合阶段是最大的。这两种蛋白质在大小和结构域上相似；然而，尽管总体上相似，肌铁蛋白已知的生理功能与异铁蛋白并不重叠。本文首次展示了人肌铁蛋白C2A在1.9埃分辨率下与两个二价阳离子结合的x射线晶体结构，并将其三维结构和膜结合活性与dysferlin C2A进行了比较。我们发现，虽然dysferlin C2A以Ca2+依赖的方式结合膜，Ca2+结合是这种相互作用的限速动力学步骤。另一方面，Myoferlin C2A结合两个钙离子的亲和力比dysferlin C2A低3倍；令人惊讶的是，肌钙蛋白C2A仅与含有高比例磷脂酰丝氨酸的磷脂混合物轻微结合。(C) 2019 Elsevier Ltd.版权所有。
Dysferlin has been implicated in acute membrane repair processes, whereas myoferlin's activity is maximal during the myoblast fusion stage of early skeletal muscle cell development. Both proteins are similar in size and domain structure; however, despite the overall similarity, myoferlin's known physiological functions do not overlap with those of dysferlin. Here we present for the first time the X-ray crystal structure of human myoferlin C2A to 1.9 angstrom resolution bound to two divalent cations, and compare its three-dimensional structure and membrane binding activities to that of dysferlin C2A. We find that while dysferlin C2A binds membranes in a Ca2+-dependent manner, Ca2+ binding was the rate-limiting kinetic step for this interaction. Myoferlin C2A, on the other hand, binds two calcium ions with an affinity 3-fold lower than that of dysferlin C2A; and, surprisingly, myoferlin C2A binds only marginally to phospholipid mixtures with a high fraction of phosphatidylserine. (C) 2019 Elsevier Ltd. All rights reserved.